Patients who abuse ethanol suffer from a global deficiency in immune responses, which leaves them more susceptible to infection with such pathogens as Mycobacterium tuberculosis and Hepatitis C Virus. The primary target of ethanol is the liver, where it results in inflammation, fibrosis, liver failure and hepatocellular cancer. Therefore, to gain insight into the immune effects of ethanol, we will test its impact on the livers resident antigen-presenting cells. We hypothesize that the effect of ethanol is to induce innate immune activation, resulting in Interferon synthesis; and that such Interferon is the primary driver of the expression of immunosuppressive molecules. We term this model Adaptive Liver Tolerance, in view of its similarity to Adaptive Resistance, a form of immune tolerance induced by some cancers. Our Preliminary Data both reveal the up-regulation of some immunosuppressive genes, and the induction of Type 1 Interferon genes, consistent with the proposed mechanism. In this Exploratory/Developmental R21 proposal, we will test whether the Adaptive Liver Tolerance model explains the effects of ethanol on immunity. First we will detect changes in the expression of pro-inflammatory versus immunosuppressive genes in liver antigen-presenting cells, both via cell isolation and using a novel experimental tool, the RiboTag mouse, to measure gene expression in specific cell types in situ. Second we will test how far each group of genes depends on Interferon signaling. Third, we will determine which liver antigen-presenting cells are impaired in antigen-presentation, and finally whether Interferon-dependent immunosuppressive molecules are responsible for impaired antigen presenting cell function following ethanol administration. Taken together, these experiments will decisively test a novel hypothesis that can explain the immune compromise associated with ethanol excess. If the hypothesis is supported, future research will map the cellular and molecular pathways of such immune tolerance, test its interaction with viral hepatitis, and identify therapeutic targets.